FLUOROURACIL CHEMOTHERAPY FOR COLORECTAL CANCER

Pharmacology of fluorouracil
Fluorouracil has remained the cornerstone chemotherapy for
colorectal cancer for over 40 years. It is a prodrug that is
converted intracellularly to various metabolites that bind to the
enzyme thymidylate synthase, inhibiting synthesis of thymidine,
DNA, and RNA. Increasing understanding of the molecular
pharmacology of fluorouracil has led to the development of
strategies to increase its efficacy.
The first strategy to be tested was coadministration with the
immunostimulatory, antihelminthic drug levamisole, but despite
promising early results, recent trials have not convincingly
shown significant improvements in outcome compared with
fluorouracil alone. In addition, no persuasive mechanism for the
assumed synergism between fluorouracil and levamisole has
been found.
In contrast, addition of folinic acid increases and prolongs
the inhibition of the target enzyme (thymidylate synthase) and
seems to confer improved clinical outcome compared with
fluorouracil alone in advanced disease and when used in
adjuvant therapy.
The side effects of chemotherapy based on fluorouracil vary
according to the regimen (most commonly given as bolus
intravenously daily for 5 days every 4 weeks or bolus weekly).
They include nausea, vomiting, an increased susceptibility to
infection, oral mucositis, diarrhoea, desquamation of the palms
and soles, and, rarely, cardiac and neurological toxic effects